Abstract 11905: Loss of Adrenergic and Adenosine Regulation of Extradyadic L-type Calcium Channels in Rat Atrial Myocytes in Heart Failure
It has recently become evident that discrete clusters of L-type Ca2+ channels (LTCCs) exist along the cardiomyocyte sarcolemma in association with distinct membrane structures. Such microdomain-specific localization impact channel function and regulation by a variety of neurohormonal pathways, including adrenergic and adenosine. Disruption in their subcellular targeting may contribute to the pathophysiology of cardiac diseases, including heart failure (HF). We used Ca2+ imaging and super-resolution scanning patch clamp to examine microdomain-specific regulation of LTCCs in atrial myocytes isolated from control and 16-weeks post-MI HF rats. In control, β1 adrenergic receptors (β1ARs) stimulation (ISO 100 nM and β2AR antagonist ICI 50 nM) enhanced spontaneous Ca2+ release events while the following adenosine A1 receptors (AdoA1Rs) stimulation (2'-MeCCPA 200 nM) abolished β1ARs effects. Non-localized β1ARs stimulation (ISO 2 μM and ICI 50 nM in external solution) activated single LTCCs in both t-tubules and on the crest of sarcolemma, increasing LTCC occurrence and enhancing their open probability and amplitude. Local AdoA1R stimulation through the pipette (10 μM) on β1ARs-pretreated cells completely abolished β1ARs effects. In HF, both β1ARs and AdoA1R effects on LTCCs were preserved in t-tubules and lost on the crest. Similar, the effect of β1AR stimulation on spontaneous Ca2+ release events was significantly reduced in HF (28% vs 134% in HF vs control, P<0.01) and the anti-adrenergic effect of AdoA1R was lost (8% vs 84% in HF vs control, P<0.01), despite up-regulation of β1 and AdoA1Rs mRNA. No changes in caveolae density were observed in HF (4.6±0.4 caveolae/μm vs 3.7±0.5 caveolae/μm for HF vs control, P=0.167). Our findings provide the first direct evidence for microdomain-specific remodeling of LTCC regulation by adrenergic and adenosine receptors in HF which could be linked to local disruption in the interactions between LTCCs and their cellular microenvironment. This extends beyond the classical concept of electrical remodeling, stressing the involvement of alteration of spatial compartmentation of ion channels and receptors in addition to classical concepts of changes in protein expression and post-translational modifications.
Author Disclosures: A.V. Glukhov: None. M. Balycheva: None. J. Sanchez-Alonso: None. N. Bhogal: None. I. Diakonov: None. M. Mazzola: None. G. Faggian: None. J. Gorelik: None.
- © 2015 by American Heart Association, Inc.